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Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes

Nature volume 432, pages 1027–1032 (2004)Cite this article

Abstract

The regulation of fat and glucose metabolism in the liver is controlled primarily by insulin and glucagon. Changes in the circulating concentrations of these hormones signal fed or starvation states and elicit counter-regulatory responses that maintain normoglycaemia. Here we show that in normal mice, plasma insulin inhibits the forkhead transcription factor Foxa2 by nuclear exclusion and that in the fasted (low insulin) state Foxa2 activates transcriptional programmes of lipid metabolism and ketogenesis. In insulin-resistant or hyperinsulinaemic mice, Foxa2 is inactive and permanently located in the cytoplasm of hepatocytes. In these mice, adenoviral expression of Foxa2T156A, a nuclear, constitutively active Foxa2 that cannot be inhibited by insulin1, decreases hepatic triglyceride content, increases hepatic insulin sensitivity, reduces glucose production, normalizes plasma glucose and significantly lowers plasma insulin. These changes are associated with increased expression of genes encoding enzymes of fatty acid oxidation, ketogenesis and glycolysis. Chronic hyperinsulinaemia in insulin-resistant syndromes results in the cytoplasmic localization and inactivation of Foxa2, thereby promoting lipid accumulation and insulin resistance in the liver. Pharmacological intervention to inhibit phosphorylation of Foxa2 may be an effective treatment for type 2 diabetes.

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Figure 1: Insulin induces phosphorylation and nuclear exclusion of Foxa2 in mouse livers.
Figure 2: Metabolic measurements in Srebp-1c mice expressing Foxa2.
Figure 3: Improved hepatic insulin sensitivity in ob/ob mice infected with Ad–T156A.
Figure 4: Decreased β-oxidation and ketogenesis and reduced hepatic insulin sensitivity in Foxa2+/- mice.

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Acknowledgements

We thank J. Kruetzfeld for advice and comments. These studies were supported by grants from the NIH (M.S.), by an unrestricted grant from Bristol Myers Squibb (M.S.) and by the Howard Hughes Medical Institute (J.M.F.).

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Authors and Affiliations

  1. Laboratory of Metabolic Diseases, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Christian Wolfrum, Edlira Luca & Markus Stoffel

  2. Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Esra Asilmaz & Jeffrey M. Friedman

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Correspondence to Markus Stoffel.

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Supplementary information

Supplementary Table 1

Fold regulation of gene expression in Ad-GFP vs. Ad-Foxa2T156A infected livers of wildtype (C57BL/6J) mice. One table, description for table in separate file. (PDF 47 kb)

Supplementary Table 2

Fold-regulation of gene expression in Ad-GFP and Ad-T156A infected livers of wildtype (C57BL/6J), ob/ob, srebp-1c and high fat diet-induced obese (HF) mice. One table, description for table in separate file. (PDF 47 kb)

Supplementary Table 3

Fold regulation of gene expression in Ad-GFP vs. Ad-Foxa2T156A infected livers of wildtype (C57BL/6J) mice using AffymetrixTM oligonucleotide expression arrays M430A and B. One table, description for table in separate file. (XLS 201 kb)

Supplementary Figure 1

Gene expression of Irs1 and Irs2 in livers of C57/B6, ob/ob, Srebp and HF diet mice. One figure, description included under figure. (PDF 104 kb)

Supplementary Figure 2

Nuclear localization (a), electrophoretic shift analysis (EMSA)(b) in livers of ob/ob, Srebp and HF diet mice. (c) Immunoblots of total and phosphorylated Foxa2 and Foxo1 in liver nuclear and cytoplasmic extracts of starved and fed wioldtype mice, starved Ad-t156A treated mice, and starved Ad-t156A and Ad-GFP injected animals. Three figures, description included under figure. (PDF 704 kb)

Supplementary Figure 3

Metabolic measurements in wildtype (Wt), ob/ob and high fat diet induced obese mice (HF) infected with Ad-GFP (black), Ad-Foxa2 (red) and Ad-T156 (green) over a period of 14 days postinfection. Total of 21 figures, description separate. (PDF 73 kb)

Supplementary Figure 4

Foxa-2 is a transcriptional activator of β-oxidation, ketogenesis and glycolytic gene promoters in vitro. a, HepG2 cells were transfected with the Foxa2 or Foxo1 expression vectors, pCMV-β-Gal and the luciferase reporter genes harboring the indicated promoters. b, In vivo binding of Foxa2 to conserved Foxa binding sites of promoters. The association of Foxa2 and Foxo1 and β-oxidation, ketogenesis, glycolytic and gluconeogenesis gene promoters was measured by ChIP assay. Two figures, description separate. (PDF 307 kb)

Description for Supplementary Table 1 (DOC 19 kb)

Description for Supplementary Table 2 (DOC 20 kb)

Description for Supplementary Table 3 (DOC 19 kb)

Description for Supplementary Figure 3 (DOC 20 kb)

Description for Supplementary Figure 4 (DOC 21 kb)

Supplementary Methods

Reverse transcriptase-PCR and Affymetrix gene array. (DOC 21 kb)

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Wolfrum, C., Asilmaz, E., Luca, E. et al. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432, 1027–1032 (2004). https://doi.org/10.1038/nature03047

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